tbuckley/cabot-search huggingface dataset:
Digital Health Applications in Oncology: An Opportunity to Seize
Authors: Ravi B Parikh, Karen M Basen-Enquist, Cathy Bradley, Deborah Estrin, Mia Levy, J Leonard Lichtenfeld, Bradley Malin, Deven McGraw, Neal J Meropol, Randall A Oyer, Lisa Kennedy Sheldon, Lawrence N Shulman
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Digital health advances have transformed many clinical areas including psychiatric and cardiovascular care. However, digital health innovation is relatively nascent in cancer care, which represents the fastest growing area of health-care spending. Opportunities for digital health innovation in oncology include patient-facing technologies that improve patient experience, safety, and patient-clinician interactions; clinician-facing technologies that improve their ability to diagnose pathology and predict adverse events; and quality of care and research infrastructure to improve clinical workflows, documentation, decision support, and clinical trial monitoring. The COVID-19 pandemic and associated shifts of care to the home and community dramatically accelerated the integration of digital health technologies into virtually every aspect of oncology care. However, the pandemic has also exposed potential flaws in the digital health ecosystem, namely in clinical integration strategies; data access, quality, and security; and regulatory oversight and reimbursement for digital health technologies. Stemming from the proceedings of a 2020 workshop convened by the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine, this article summarizes the current state of digital health technologies in medical practice and strategies to improve clinical utility and integration. These recommendations, with calls to action for clinicians, health systems, technology innovators, and policy makers, will facilitate efficient yet safe integration of digital health technologies into cancer care.
Abstract 2093: PEGylated IL-2 with enhanced anti-tumor efficacy and safety profile
Authors: Yuntao Song, Hui Li, Wei Zhang, Dayan Fu, Meng Xu
Journal: Cancer Research (2022)

Abstract Introduction: Interleukin-2 (IL-2) can activate and expand tumor killing lymphocytes. High doses of IL-2 are needed to activate CD8+ T cells. Severe toxic side effects associated with high doses, as well as the poor PK profile of IL-2, have limited its clinical usage. Various strategies have been employed to prolong half-lives of IL-2 and enable selectivity or bias towards receptor binding to reduce toxicity and maintain good efficacy. Among these, certain PEGylation strategies have generated promising clinical results, but also showed some major limitations. We report a unique PEGylation strategy to produce PEGylated IL-2 with a therapeutic window more than two times larger than the reference PEGylated IL-2. Methods: CT26 murine syngeneic model was used for evaluation of in vivo efficacy and safety. Each 6-8 weeks old female BALB/c mouse was inoculated subcutaneously in the right front flank region with CT26 tumor cells (5 x 105). Tumors were allowed to grow to mean size ~110 mm3 before randomization and treatment. Body weights and tumor volumes were measured three times per week. The tumor-free mice at the end of the study were re-challenged with CT26 colon tumor cells on the left side. Results: Utilizing our proprietary PEGylation technology, rhIL-2 was covalently connected with multiple PEG polymers through releasable linkers (RL). The releasable linkers are designed to modulate the release rate of the active IL-2 species. In CT26 syngeneic mouse model, CS-PEG-IL-2 showed significantly enhanced efficacy and safety over IL-2 and reference PEGylated IL-2. rhIL-2 (2 mg/kg, bid x 5, two cycles, i.p.) resulted in complete response (CR) in one out of eight (1/8) mice, while 3 mg/kg dose resulted in death in 8/8 mice. With the reference PEGylated IL-2, 3/8 CR were obtained at 3 mg/kg dose (q1w x 4, i.v.), and 6 mg/kg dose resulted in death in 8/8 mice. Whereas, with three CS PEGylated IL-2 analogs, 5/8 and 6/8 CR were achieved at 3 mg/kg and 6 mg/kg dose respectively, and no obvious toxicity was observed even at the highest dose. After re-challenged with another inoculation of CT26 cancer cells, the CR mice remained tumor-free until the end of the study at day 158. Conclusions: CS unique PEGylation strategy generated PEG-IL-2 with superior anti-tumor efficacy and safety profiles. Preclinical results support clinical evaluation of this novel class of PEGylated IL-2 analogs. Citation Format: Yuntao Song, Hui Li, Wei Zhang, Dayan Fu, Meng Xu. PEGylated IL-2 with enhanced anti-tumor efficacy and safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2093.
Abstract 2229: Targeted locus amplification based sequencing for mapping viral integration sites in human papillomavirus positive head and neck squamous cell carcinomas
Authors: Imke Demers, Harini Balaji, Harma Feitsma, Irinia Sergeeva, Joost Swennenhuis, Nora Wuerdemann, Steffen Wagner, Bernd Kremer, Christian Huebbers, Jens Peter Klussmann, Ernst-Jan Speel
Journal: Cancer Research (2022)

Abstract Background: Human papillomavirus (HPV) infections are the principal cause of cervical cancers, subsets of anogenital and head and neck cancers (HNC). During persistent infection, viral DNA integration into the host genome may occur, which is suggested to affect carcinogenesis. One of the most critical limitations of currently used HPV integration detection techniques (PCR-based or NGS-based) is their application to FFPE material, because of DNA fragmentation. The aim of this study was to assess HPV integration in HPV-positive HNSCC cell lines and FFPE tissue comparing the new Targeted Locus Amplification (TLA) technology with previously used PCR technology (APOT/DIPS). Methods: Seven HPV-positive cell lines and FFPE material of 10 HPV-positive HNSCC were used for HPV integration detection by TLA, a proximity ligation-based next-generation sequencing technique. Crosslinked DNA is digested with restriction enzymes, and re-ligated into chimeric DNA molecules. For cell lines, a PCR based HPV16 target enrichment is performed, and for FFPE material a capture-based target enrichment is performed for HPV16 and HPV18 sequences, both followed by Illumina sequencing. Results: TLA was able to sequence up to 100 kb around the target, detecting exact HPV integration loci, structural variants, and chromosomal rearrangements. In all cell lines, one or more integration sites were identified, in accordance with APOT/DIPS PCR data and the literature. In the FFPE tissue samples, TLA identified integrated HPV in 6 out of 10 tumors, with simple and complex integration patterns. In general, TLA confirmed PCR data and detected additional integration sites. Conclusion: TLA provides the opportunity for reliable and robust detection of HPV integration in HNSCC cell lines and FFPE tissue. This new sequencing technology could be a useful tool for further research on HPV integration in disease and patient outcome and eventually in clinical diagnostics. Citation Format: Imke Demers, Harini Balaji, Harma Feitsma, Irinia Sergeeva, Joost Swennenhuis, Nora Wuerdemann, Steffen Wagner, Bernd Kremer, Christian Huebbers, Jens Peter Klussmann, Ernst-Jan Speel. Targeted locus amplification based sequencing for mapping viral integration sites in human papillomavirus positive head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2229.
Abstract 6308: Antitumor effects of RBPJ Inhibitor-1 on osteosarcoma cells
Authors: Dakota Callahan, Leetoria Hinojosa, Haydee M. Torres, Jianning Tao
Journal: Cancer Research (2022)

Abstract Osteosarcoma (OS) is the most common primary malignancy of the bone in adolescents and children with limited treatment options. Drug resistance to current therapy together with severe side effects urgently calls for alternative treatment strategies targeting critical cancer signaling pathways. Recently, our and other studies suggest that hyperactivation of Notch signaling contributes to the pathogenesis of human and murine OS, and its inhibition may be a therapeutic approach for the treatment of OS. Notch pathophysiological activity involves activated Notch (i.e. NICD, the notch intracellular domain) forming a nuclear complex with DNA-binding factors and coactivators such as recombination signal binding protein for immunoglobulin kappa J region (RBPJ). This evolutionary conserved mechanism is involved in the maintenance and survival of cancer stem cells, which can govern various cell activities like metastasis and chemoresistance. This study aims to examine the in vitro effects of targeting the NICD-RBPJ interaction using a small molecular inhibitor of the RBPJ (RIN1) on osteosarcoma cell lines. We found that treatment of 10 µM RIN1 on SJSA-1 (ATCC, CRL-2098), a human osteosarcoma cell line with a high Notch activity, can significantly decrease cell proliferation at 48 and 72 hours (h). We also found that at 10 µM of RIN1 affects SJSA-1 migration using a Boyden chamber-based cell system at 24 h, a time point where we find minimal contribution from an effect on cell proliferation. Treatment with RIN1 can block SJSA-1 clonogenicity, but we showed that it has limited ability to block SJSA-1 cell invasion. Treatment with RIN1 does not initiate or enhance the osteoblast-like differentiation of SJSA-1. Notch target genes HEY1 and CyclinD1 was significantly modulated in SJSA-1 cells upon treatment in a Notch-independent manner. Interestingly, treatment with RIN1 on SJSA-1 decreases SOX2 protein expression, a well-known cancer stem cell marker, and upregulates tumor suppressor RB1 protein expression. Ongoing studies include additional cellular function assays and RNA-seq transcriptomic analysis of RIN1’s effect on two Notch-dependent cancer cell lines including MB 157 (ATCC, CRL-7721) and T29 in its activating context. In summary, RIN1 has been shown to have a significant effect on the different cell behaviors of human osteosarcoma, which may eventually facilitate with the treatment of patients that have metastatic disease. Citation Format: Dakota Callahan, Leetoria Hinojosa, Haydee M. Torres, Jianning Tao. Antitumor effects of RBPJ Inhibitor-1 on osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6308.
Abstract 3504: QL415, a tumor targeted IL-15 fusion protein stimulating both lymphoid and myeloid immune cells for optimal anti-tumor immune response
Authors: Irene Tang, Lauren Schwimmer, Monica Jin, Shenda Gu, Wei Wei Prior, Arianne Capacio, Hieu V. Tran, Allan Chan, Anna McClain, Shihao Chen, Chuanzeng Cao, Xiaoran Wu, Yanling Xu, Dongmei Guan, Xi Chen, Xianli Su
Journal: Cancer Research (2022)

Abstract Cytokines are potent stimulators of the immune system and have long been investigated and used as therapeutics to treat cancer. However, free cytokines have short half-life and the lack of tumor targeting often results in systemic toxicity. IL-15 is a stimulatory cytokine that shares the common beta and gamma receptors with IL-2. In contrast to IL-2, IL-15 is more selective for NK and effector memory T cells, with less proliferative effect on Tregs, making it a more preferred therapeutic candidate for cancer. QL415 is an anti-PD-L1 x IL-15 fusion protein designed to enhance tumor accumulation and prolong blood circulation, thereby widening the therapeutic window. IL-15 and IL-15 receptor alpha sushi domain are covalently linked to the C-terminus of our proprietary PD-L1 antibody. Fc-mediated effector functions were ablated using mutations in the CH2 domain, to prevent depletion of effector immune cells. In vitro studies showed QL415 to be highly potent in promoting proliferation and pSTAT5 signaling of IL-15 -responding NK92 and M07e cells. QL415 selectively induced proliferation of NK and CD8+ T cells from human PBMC in vitro and mouse CD8+ and NK1.1 cells in vivo. In a MC38 mouse colon cancer model expressing human PD-L1, QL401 was highly effective in suppressing tumor growth, in contrast to PD-L1 monoclonal antibody or a non-targeted IL-15 control. Follow up tumor rechallenge study showed protective memory against cognate MC38 but not B16F10. In a separate MC38 tumor model using a mouse surrogate molecule of QL415, immunophenotyping of antigen presenting cells offered preliminary evidence of enrichment of conventional dendritic cells 1 in the tumor draining lymph nodes. Therefore, QL415 not only directly stimulates effector immune cells, but also indirectly through antigen presenting cells, promotes robust anti-tumor response. In non-human primates, Q415 was tolerated up to 1.5 mg/kg, well above the effective therapeutic dose. In light of these favorable preclinical efficacy and safety results, a phase 1 dose escalation and expansion study has been initiated to evaluate the safety, tolerability, and early efficacy of QL415. Citation Format: Irene Tang, Lauren Schwimmer, Monica Jin, Shenda Gu, Wei Wei Prior, Arianne Capacio, Hieu V. Tran, Allan Chan, Anna McClain, Shihao Chen, Chuanzeng Cao, Xiaoran Wu, Yanling Xu, Dongmei Guan, Xi Chen, Xianli Su. QL415, a tumor targeted IL-15 fusion protein stimulating both lymphoid and myeloid immune cells for optimal anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3504.
The Slc25a47 locus is a novel determinant of hepatic mitochondrial function implicated in liver fibrosis
Authors: Nadia Bresciani, Hadrien Demagny, Vera Lemos, Francesca Pontanari, Xiaoxu Li, Yu Sun, Hao Li, Alessia Perino, Johan Auwerx, Kristina Schoonjans
Journal: Journal of Hepatology (2022)
Abstract 1373: PeptidePCR: Direct identification of cancer vaccine targets from scant clinical samples
Authors: Sri H. Ramarathinam, Pouya Faridi, Angela Peng, Pacman Szeto, Nicholas C. Wong, Andreas Behren, Mark Shackleton, Anthony W. Purcell
Journal: Cancer Research (2022)

Abstract Background: Peptides presented by Human Leukocyte antigen (HLA) class I and II molecules form an important component of the adaptive immune response against tumors. Identifying HLA-bound peptides is therefore crucial to understand the specificity of T cell responses in cancer. Due to sample limitations, it is often difficult or impossible to confirm epitope presentation in clinical biopsy material. To develop truly personal medicine, target epitopes need to be directly identified or validated in patient tumors at the peptide antigen level. Methodology: We have developed a microscale HLA immunoprecipitation protocol which when combined with a tandem mass tag (TMT)-based barcoding approach was able to identify HLA-bound peptides. HLA-complexes were affinity purified from either cultured cells, patient-derived xenograft or melanoma biopsies and the peptide cargo was tagged using TMT barcodes and analyzed using high-resolution mass spectrometry. Like primers in PCR, the carrier peptides and multiplexing of samples amplifies the signal enabling sensitive detection. Results: By using this strategy, we identified HLA-bound peptides from as few as ~1000 cultured cells. We demonstrate the clinical utility of this approach by confirming the presentation of around 1000 peptides from a challenging melanoma biopsy (~1-20mg in total), including 11 well-known T-cell response-inducing epitopes and other potential epitopes derived from Melanoma-associated antigens and neoantigens. Conclusion: This strategy will be useful for studying peptidome subsets in other clinical samples where the amount of tissue available via sampling is limiting, including biopsies taken for autoimmune diseases and infections, or to sample rare cell types in tissue/cell samples, such as different antigen-presenting cell subsets. The approach can directly isolate antigens that are already presented by HLA molecules, thereby increasing the precision of personalized approaches to cancer treatment with less than 1-week turnaround times. Citation Format: Sri H. Ramarathinam, Pouya Faridi, Angela Peng, Pacman Szeto, Nicholas C. Wong, Andreas Behren, Mark Shackleton, Anthony W. Purcell. PeptidePCR: Direct identification of cancer vaccine targets from scant clinical samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1373.
Abstract 6324: Development and characterization of Ewing Sarcoma lung metastasis model
Authors: Atreyi Dasgupta, Lyazat Kurenbekova, Tajhal Patel, Jason T. Yustein
Journal: Cancer Research (2022)

Abstract Introduction: Ewing Sarcoma (EwS) is the second most common bone tumor in children. At diagnosis, approximately 20-25% of patients with EwS have metastatic disease. While systemic chemotherapy, along with surgery and/or radiotherapy, has significantly increased the survival rate of patients with localized disease, metastatic Ewing sarcoma (EwS) has an extremely poor overall survival with a 5-year survival rate of approximately 20-30%. This prognosis has not changed in the last several decades. Thus, there is an imperative need to focus particularly on mechanisms of metastatic growth and progression and to identify and target the underlying intrinsic and extrinsic molecular features. Unfortunately, presently there is no reliable engineered mouse model to functionally study EwS development and metastasis. Using two independent EwS cell lines, we have developed highly aggressive, lung-specific metastatic models that show mechanistic overlap with human patient tumor data and are valuable resources to further study and target metastatic EwS. Approach: Using a serial transplantation approach, we generated lung specific metastatic lines by repeated intra-tibial injection of two commonly used EwS cell lines (A673 and TC71), allowing metastatic foci to form, followed by dissociation and subsequent re-injection into the tibia. We repeated this 5 times to generate highly aggressive lung-specific metastatic cell lines. As a proof of principle, when equal numbers of GFP+ parental cells and mCherry+ lung metastatic cells are injected into the tibia in NSG mice they form primary tumors with red and green cells, while the metastatic lesions in lungs are almost exclusively mCherry+. A multi-omics approach including glycoproteomics, secretome, and transcriptomic analysis were then used to characterize these cells and compare them with patient tumor samples. Results: Integration of focused proteomics and glycoproteomics data revealed upregulation in AXL, MEK6, STAT1, and STAT3 proteins and phosphoproteins in metastatic lesions. Focused RNA profiling with Nanostring technologies using formalin-fixed paraffin-embedded (FFPE) slides of patient tumor samples revealed increased expression of several other upstream genes that signal through STAT1, including IL-6, IKK-β, TRAF-6, and Myd88. In addition, upregulation in factors involved in tumor invasive front such as Furin, TIMP-2, MMP-2, and MMP-14 were also noted. We are currently in the process of further validating some of the key regulators using larger set of patient derived tumors and by targeting them in orthotopic mouse models. Citation Format: Atreyi Dasgupta, Lyazat Kurenbekova, Tajhal Patel, Jason T. Yustein. Development and characterization of Ewing Sarcoma lung metastasis model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6324.
Abstract 5173: Digital spatial profiling of metastatic clear cell carcinoma reveals intra-tumor heterogeneity in epithelial-mesenchymal gradient
Authors: Duncan Y.T. Wang, Tuan Zea Tan, Ya-Ting Tai, Jieru Ye, Wei-Chou Lin, Lin-Hung Wei, Ruby Y. J. Huang
Journal: Cancer Research (2022)

Abstract Intrinsic intra-tumor heterogeneity (ITH) has been linked to worse patient outcomes. The development of spatial profiling technology has enabled the deciphering of ITH with multiple analysis readouts. Advanced ovarian clear cell carcinoma (OCCC), known to harbor ITH, is chemoresistant, poor prognostic, and possesses distinct molecular and histological characteristics. However, detailed spatial information of the nature of ITH within OCCC remains unclear. Here, we utilized the NanoString Digital spatial profiling (DSP) GeoMx platform to perform multiplex protein expression analysis on tumor samples of primary and colonic metastatic sites from one advanced OCCC patient. The spatial resolution revealed the existence of an epithelial-mesenchymal (EM) gradient within the metastatic tumor but not the primary tumor, and similar EM gradient was not observed within the primary tumor. The EM gradient exhibited a distinct pattern from the periphery to the core of the metastatic tumor. Compared to tumor cells at the primary site, there was an intermediate zone in between the tumor periphery and the tumor core in the colonic metastasis with differential expression patterns of pan-cytokeratin (PanCK), fibronectin (FN), smooth muscle actin (SMA), neural cell adhesion molecule (NCAM), integrin alpha X (ITGAX), and Ki-67. Our study provides the first spatially resolved in situ evidence of intermediate or hybrid EM states within the tumor samples of similar morphology. This not only demonstrates the promising applications of spatial profiling in precision medicine but also provides an unprecedented view of the EM gradient during the progression of cancer such as OCCC. Citation Format: Duncan Y.T. Wang, Tuan Zea Tan, Ya-Ting Tai, Jieru Ye, Wei-Chou Lin, Lin-Hung Wei, Ruby Y. J. Huang. Digital spatial profiling of metastatic clear cell carcinoma reveals intra-tumor heterogeneity in epithelial-mesenchymal gradient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5173.